Hypertension is a common condition associated with disease in multiple organ systems, including the cardiovascular, cerebrovascular, and renal systems. The etiology of essential hypertension is unknown. While many factors have been implicated in the pathogenesis of hypertension, the kidney plays the primary role in long-term blood pressure control. Pressure-induced natriuresis (P-N), wherein an increase in arterial blood pressure leads to an increase in urinary sodium and water excretion, is the dominant mechanism for this control. The experiments outlined in this application will test the hypothesis that extracellular renal interstitial cyclic guanosine 3'5'-monophosphate (RIcGMP) is a molecule that plays a critically important role in the mechanism of P-N. The experiments pertaining to the first specific aim explore one mechanism by which this may occur. Those experiments addressing the second specific aim will provide preliminary evidence that two agents which augment RIcGMP may be useful as therapeutic agents in treating human hypertension. Aim 1. To test the hypothesis that extracellular RIcGMP mediates the rise in renal interstitial hydrostatic pressure (RIHP) observed after an increase in renal perfusion pressure (RPP) and is necessary for the resulting P-N. Aim 2. To test the hypothesis that increased extracellular RIcGMP augments P-N: (1) by activating soluble guanylyl cyclase (sGC), which generates cGMP from guanosine triphosphate. (2) by inhibiting phosphodiesterase V (PDE V), which specifically hydrolyzes cGMP. A unique microdialysis technique for measuring renal interstitial (Rl) products in vivo in the rat will be utilized. A microinfusion method wherein various pharmacologic agents can be infused directly into the Rl compartment will also be used. This research will lead to a more complete understanding of the underlying cause of essential hypertension. It will lead to better, more specific therapies for the more than 70 million Americans with high blood pressure. [unreadable] [unreadable] [unreadable]